Therapeutic compositions for the potentiation of barbiturates and analgesics



THERAPEUTIQ CGMPOSH'E'EGN? FQR THE PUTEN- gIAIlQN ()F BAREETURATES AND ANALGE- 1C Arthur Ernest Wilder Smith, 18 Chemin ties Lilas Blames, Geneva, Switzerland No Drawing. Filed Jan. 29, 1962, Ser. No. 169,590

(Ilaims priority, application "Great Britain Feb. 7, 1961 11 Claims. (Ci. 167-52) This invention is concerned with improvements in or relating to therapeutic compositions more particularly compositions containing one or more pharmacologically active barbiturates ormorphinic analgesics.

This application is a eontinuation-in-part of my application Serial No. 764,756, filed October 2, 1958, now abandoned.

As is known, pharmacologically active barbiturates and morphinic analgesics suffer from a number of disadvantages which limit their use in therapeutics. Thus, there may be an inconveniently long latent period after administration of a barbiturate before it takes efiect and the sedation produced may not be of the required depth or length. The toxicity of some barbiturates is marked and seriously limits the dose which can be administered. Morphinic analgesics alsoin-general possess marked toxic properties, which limits the dose which can be used.

I have now found, however, that compounds of the general formulae set out below markedly potentiate the pharmacological activity of barbiturates and of morphinio analgesics. In the case of barbiturates this potentiation manifests'itself byincreasing the soporific and/or antiepileptic etfect of barbiturates and also in some cases by shortening the latent period which elapses after the administration of the barbiturate before it takes effect. The compounds mentioned also in general lower the acute toxicity of barbiturates and render the therapeutic indices more favourable. In the case of morphinic analgesics the ratio of analgesic action to toxicity and respiratory depression is increased thereby enabling more powerful analgesic action to be safely achieved.

It is thus possible to formulate barbiturate and morphinic analgesic compositions containing compounds of the general Formulae I-IV which compositions have a far lower rate of toxicity to pharmacological action than the barbiturates and morphinic analgesics themselves, thus enabling the barbiturates and morphinic analgesics to be administered in a lower dose toobtain the same pharmacological efiect.

According to the invention, therefore, I provide therapeutic compositions comprising at least one pharmacologically-active compound chosen from the group comprising barbiturates and morphinic analgesics together with one or more compounds of the following (general "formulae:

R 0 o-Qnno o emotions ii,$,8l2 ?atenteti May id, 1953 was ROOC- -NHCOCHzGHOHr (in which R, R and R represent alkyl groups having from 1 to 5 carbon atoms, X represents a group ROO C-, a hydrogen atom or a halogen atom and Y is a halogen atom or a hydrogen atom) and/ or non-toxic salts thereof.

Suitable non-toxic salts of both morphinic analgesics and the potentiating compound include particularly addition salts with acids which are physiologically compatible at the dosages employed, examples of such acids being hydrochloric, hydrobromic, sulphuric, citric, tartaric, acetic, fumaric, and maleic acids.

, In the above general Formulae I and IV R is preferably a methyl, ethyl, n-propyl or n-butyl group. In general Formula I R and R are preferably both ethyl groups.

The substituted butyric acid anilides of Formulae l to IV can be readily prepared by reacting the appropriately substituted crotonic acid anilide with an amine R R NH, such method being described, for example, in my US. Patent 2,801,247 and in my British Patent No. 801,405.

As specific preferred examples of compounds of general Formulae IIV which we have found to be particularly suitable for potentiation of the action of barbiturates may be mentioned the following:

and

N-(fl-pyrrolidino)butyryl-p-amino benzoic acid ethyl ester N(l3-pyrrolidin0)-butyryl-p-amino benzoic acid methyl ester N-(fi-piperidino)-butyryl-p-arnino benzoic acid ethyl ester N-(fl-piperidino)-butyryl-p-amino benzoic acid n-butyl ester B-Pyrrolidino-butyric acid anihde fi-Pyrrolidino-butyric acid (2 4-d-ichloro anilide ,B-Pyrrolidino-butyric acid (4-chloro)-am'lide The barbiturate or barbiturates to be included in the compositions according to the invention may be any desired barbiturate such as phenobarbitone, hexobarbitone, secobarbitone, pentobarbitone and butobarbitone. By the term pharmacologically active when used here n in relation to barbiturates is meant barbituric acid and related compounds which have a soporific and/ or antiepileptic effect.

By the expression morphinic analgesic as used herein I mean morphine itself and analgesics structurally and/or pharmacologically related thereto including particularly but not exclusively naturally occurring substances.

Analgesics related to morphine include, for example pethidine, codeine, dihydrocodeine, oxymorphone, oxycodone, dipipanone, dextromoramide, leverphanol, hydromorphone, hydrocodone, methadone, phenazocine, propoxyphene, piminodine and anileridine.

The compositions according to the invention may be formulated together with a pharmaceutical carrier or excipient in any convenient form suitable for administration orally, parenterally or in the form of a suppository.

Thus, the compositions may be formulated in a form suitable for oral administration either in a solid or liquid form. A particularly suitable solid formulation is as tablets containing the desired barbiturate or morphinic analgesic together with the potentiation compound in an inert tablet base. In liquid form the compositions may be made up as a syrup or like preparation, which may if desired contain surface active and/ or fiavouring agents, the latter serving to mask any undesirable taste of the active components.

For parenteral administration the compositions can, for example, be made up in liquid form in pyrogen-free water, the active components preferably in such cases being presented in a water soluble form. Surface active agents may be added if desired.

In such formulations, the potentiating compounds can be present as their Water soluble salts for example as hydrochlorides, citrates or tartrates, whilst the barbiturates may for example be present as their alkali-metal salts if these are soluble; the morphinic analgesics may be present as their acid addition salts.

The proportion of the potentiating compounds to the barbiturates or morphinic analgesics present in compositions according to the invention can vary Within wide limits.

In the case of barbiturates, in general, the ratio of potentiating compound to barbiturate should be at least 0.75 and preferably at least 1.5, advantageously 1.5-3.0 parts by weight, of potentiating compound to 1 part by Weight of barbiturate.

In the case of morphinic analgesics, the proportion of the potentiating compounds to the morphinic analgesic is generally in the ratio of to 50 parts by weight of potentiating compound to 1 part by Weight of morphinic analgesic. Preferably the ratio is about -3021.

Where the compositions according to the invention contain more than one barbiturate the action of the barbiturates may well be synergistic. In this case the total dose of barbiturates given may Well be less, than if only one barbiturate is given, and in such cases the concentration of potentiating compound can be reduced accordingly.

Preferred analgesic compositions include at least one morphinic analgesic together with fi-pyrrolidino butyric acid anilide or a non-toxic salt thereof. Preferred salts include the acid fumarate (M.P. 168 C.) and, in particular, the hydrochloride (M.P. 141-2 C.) and the acid maleate (M.P. 1257 C.).

The following table gives by way of example only factors by which fi-pyrroldino butyric acid anilide potentiates the action of various morphinic analgesics as determined experimentally in rats.

In each case the fi-pyrrolidino butyric acid anilide was given in a fixed dose of 50 mg./kg. body weight intraperitoneally. The values given for potentiation are those by which the original dose of the drug may be reduced to obtain equi-analgesia when the drug is given in combination with fi-pyrrolidino-butyric acid anilide.

TABLE Potentiation Drug Factor Morphine hydrochlorlde Codeine phosphate Dihydrocodeine acid tartr Pethidine hydrochloride- (+)-Propoxyphene hydrochlor1de Sodium aspirin race-v m oossucam the following representative formulations are given by way of illustration only:

Tablet base to mgs.

In the above tablet formulations the mentioned barbiturate can be replaced by hexobarbitone, secobarbitone or pentobarbitone and the potentiating compound by N- (fi-piperidino)-butyryl-p-amino benzoic acid ethyl ester.

(5) Dihydrocodeine acid tartrate 10-15 mg., e.g. 10 mg. fi-Pyrrolidino-butyric acid anilide hydrochloride 1 200-300 mg., e.g. 200 mg. Tablet base to 500 mg.

(6) Levorphenol tartrate mg 1.5 fl-Pyrrolidino-butyric acid anilide acid maleate mg 300 Tablet base to 500 mg.

(7) Pethidine hydrochloride mg 25 fi-Pyrrolidino-butyric acid anilide acid maleate mg.... 300

Tablet base to 500 mg.

This constituent may be replaced by the acid malcate (300-325 mg).

Capsules M (l) Pentobarbitone sodium 25 N-(B-piperidino)-butyryl-p-amino-benzoic ethyl ester hydrochloride 50 Orally acceptable liquid base to 150 mgs.

(2) Butobarbitone sodium 40 N-(fi-pyrrolidino)-butyryl-p-amino benzoic acid ethyl ester 60 Liquid base to 200 mgs.

lnjectable Preparations Morphine hydrochloride "mg..- 5 ,8-pyrrolidino-butyric acid anilide acid maleate 200-300 mg., e. g. 200mg.

Water for injection ml 5 (2) Methadone hydrochloride mg 5 ,B-Pyrrolidino-butyric acid anilide acid maleeate mg 300 Water for injection ml 5 (3) 'Pethidine hydrochloride mg.. 25 fi-Pyrrolidino-butyric acid anilide acid maleate mg 300 Water for injection ml 5 This constituent may be replaced by the hydrochloride (230 mg.).

(4) A preparation suitable for intravenous injection can be made by dissolving 50 mgs. of phenobarbitone sodium and 70 mgs. of N-(fi-pyrrolidino)-butyryl-pamino benzoic acid ethyl ester hydrochloride in pyrogen free water. The phenobarbitone sodium may be replaced by any other suitable water-soluble barbiturate and any other suitable water-soluble potentiating compound may be used.

Suppositories 200 mg. suppositories can be made by mixing suitable quantities of barbiturate and potentiating compound in a suitable suppository base. A single 200 mg. suppository could have the following constitution:

Mgs. Butobarbitone 45 ,B-Pyrrolidino butyric acid anilide 70 Suppository base to 200 mgs.

ROOC- --NHOOCH2CHOH3 XQ-NHOO onu nnons (II) XNrto0om mom N Y W (III) and no o- NHC 0 omcaom in which R, R and R are each alkyl radicals containing from 1 to 5 carbon atoms, X is a member selected from the group consisting of the group ROOC-, a hydrogen atom and a halogen atom and Y is a mem ber selected from the group consisting of a hydrogen atom and a halogen atom.

2. A composition as claimed in claim 1 in which said potentiatin g compound is present in the form of its watersoluble acid addition salt.

3. A composition as claimed in claim 1 in which the pharmacologically active compound is a barbiturate and from 0.75 to 3.0 parts by weight of said potentiating compound are present for each part by weight of barbiturate present.

4. A composition as claimed in claim 3 in which said potentiating compound is -/3-pyrrolidino butyric acid anilide.

5. A composition as claimed in claim 3 in which said potentiating compound is N-(B-pyrrolidino)-butyryl-pamino 'benzoic acid ethyl ester.

6. A composition as claimed in claim 1 in which the pharmacologically active compound is a morphinic analgesic and to 50 parts by weight of potentiating compound are present for each part by weight of morphinic analgesic.

7. A composition as claimed in claim 6 in which to 30 parts by weight of potentiating compound are present for each part by weight of morphinic analgesic.

8. A composition as claimed in claim 6 in which the potentiating compound is fi-pyrrolidinobutyric acid anilide.

9. A composition as claimed in claim 8 in which the fi-pyrrolidino-butyric acid anilide is present in the form of its water-soluble acid addition salt.

10. A therapeutic composition comprising at least one pharmacologically active barbiturate selected from the group consisting of phenobarbitone, hexobarbitone, secobarbitone, pentobarbitone and butobarbitone and an efiective amount of at least one compound potentiating the activity of the pharmacologically active compound, said potentiating compound being selected from the group consisting of:

X-Q-NHCQoHZcHCHt N Y i 1 and in which R, R and R are each alkyl radicals containing from 1 to 5 carbon atoms, X is a member selected from the group consisting of the group ROOC-, a hydrogen atom and a halogen atom and Y is a member selected from the group consisting of a hydrogen atom and a halogen atom.

11. A therapeutic composition comprising at least one pharmacologically active morphinic analgesic selected from the group consisting of pethidine, codeine, dihydrocodeine, oxymorphone, oxycodone, dipipanone, dextromoramide, levorphanol, hydromorphone, hydrocodone, methadone, phenazocine, propoxyphene, piminodine and anileridine and an efiective amount of at least one compound potentiating the activity of the pharmacologically active compound, said potentiating compound being selected from the group consisting of R1 at (I) X- NHOOOHQCHCH;

| N Y i i Z 11 X-QNHQO orm mom N Y r 1 and no 0 o-Qnnoomnonom in which R, R and R are each alkyl radicals containing from 1 to 5 carbon atoms, X is a member selected from the group consisting of the group ROOC-, a hydrogen atom and a halogen atom and Y is a member selected from the group consisting of a hydrogen atom and a halogen atom.

References Cited in the file of this patent UNITED STATES PATENTS 2,657,210 Clinton Oct. 27, 1953 2,793,155 Smith May 21, 1957 2,801,247 Smith July 30, 1957 OTHER REFERENCES Beiler: Arch. Int. Pharmacodyn., November 1, 1956, CVIII, No. 2, pp. 129-134.

A.M.A. Council on Drugs, New and Nonotficial Drugs, 1958, pages 299-330. 

1. A THERAPEUTIC COMPOSITION COMPRISING AT LEAST ONE PHARMACOLOGICALLY ACTIVE COMPOUND SELECTED FROM THE GROUP CONSISTING OF BARBITURATES AND MORPHINIC ANALGESICS AND AN EFFECTIVE AMOUNT OF AT LEAST ONE COMPOUND POTENTIATING THE ACTIVITY OF THE PHARMACOLOGICALLY ACTIVE COMPOUND, SAID POTENTIATING COMPOUND BEING SELECTED FROM THE GROUP CONSISTING OF 